The Adenomatous Polyposis Coli (APC) gene was discovered through the identification of germline mutations in patients with familial APC and somatic mutations in patients with sporadic cases of colorectal carcinoma. We previously have demonstrated the existence of two large families with an attenuated form of APC, called AAPC. In AAPC families, gene carriers of the mutation develop fewer numbers of colorectal polyps than do patients with classical APC and if colorectal cancer occurs, the average age of onset in AAPC families occurs later than in APC. A hallmark feature of AAPC gene carriers is the large variation in adenomatous polyp number observed within the same family. We are interested in testing the hypothesis that this variation in phenotype is due to genes that modify the expression of the APC gene. Two loci have been identified that modify the murine APC phenotype (multiple intestinal neoplasia, MIN). The first locus, MOM-1, reduces the number and size of intestinal neoplasias that develop in Min mice. Secondly, a mutations in the murine methyltransferase gene also attenuates the Min phenotype. Three additional loci that alter the susceptibility to drug-induced (non-APC/MIN) tumorigenesis in mice also have been identified. In an attempt to discover modifying gene(s) in our two large, well characterized families, we will use genetic analysis to identify modifying loci. Our primary method of analysis will be the non-parametric linkage (NPL) method that does not require a specific genetic model. We will initially choose genetic markers in regions of the genome where candidate genes are known to reside. If any of these regions show evidence for suggestive linkage. we will then search for mutations within coding sequences of any candidate genes that localized to the critical region. If no positive or suggestive linkage results are found in this initial limited search, we will then carry out a complete genome-wide search for a modifying gene with a set of 300 highly polymorphic markers. Discovery of one or more major modifying loci of the APC gene would a significant advance in understanding the biochemical mechanisms of this important polyp-producing gene.